Calorie restriction modulates the transcription of genes related to stress-response and longevity in human muscle: the CALERIE study

Authors: DAS, JAYANTA - National Institutes Of Health (NIH); BANSKOTA, NIRAD - National Institute On Aging (NIA, NIH); CANDIA, JULIAN - National Institutes Of Health (NIH); GRISWOLD, MICHAEL - University Of Mississippi Medical Center; ORENDUFF, MELISSA - Duke University School Of Medicine; DE CABO, RAFAEL - National Institutes Of Health (NIH); CORCORAN, DAVID - University Of North Carolina; DAS, SAI KRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DE, SUPRIYO - National Institutes Of Health (NIH); HUFFMAN, KIM - Duke University School Of Medicine; KRAUS, VIRGINIA - Duke University School Of Medicine; KRAUS, WILLIAM - Duke University School Of Medicine; MARTIN, CORBY - Pennington Biomedical Research Center; RACETTE, SUSAN - Washington University School Of Medicine; REDMAN, LEANNE - Pennington Biomedical Research Center; SCHILLING, BIRGIT - Buck Institute For Age Research; BELSKY, DANIEL - Columbia University; FERRUCCI, LUIGI - National Institute On Aging (NIA, NIH)

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2023
Publication Date: 10/12/2023
Citation: Das, J.K., Banskota, N., Candia, J., Griswold, M.E., Orenduff, M., De Cabo, R., Corcoran, D.L., Das, S., De, S., Huffman, K.M., Kraus, V.B., Kraus, W.E., Martin, C.K., Racette, S.B., Redman, L.M., Schilling, B., Belsky, D.W., Ferrucci, L. 2023. Calorie restriction modulates the transcription of genes related to stress-response and longevity in human muscle: The CALERIE study. Aging Cell. https://doi.org/10.1111/acel.13963.
DOI: https://doi.org/10.1111/acel.13963

Interpretive Summary: Aging comes with many different physical changes, including loss of muscle. Previous studies in animals have identified calorie restriction as a way to slow down aging, in part by helping to maintain healthy muscles. The aim of this study was to find a similar connection between calorie restriction and healthy muscle maintenance in humans. The study used strength test data and biological analyses of muscle samples from participants from The Comprehensive Assessment of Long term Effects of Reducing Intake of Energy (CALERIE), a trial examining the effects of calorie restriction in young and middle age, healthy men and women without obesity. The study showed that calorie restriction had a positive effect on the biological mechanisms that maintain healthy muscle in humans. Many of the genetic mechanisms that link calorie restriction to healthy muscle maintenance are also shared between animals and humans.

Technical Abstract: The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear. We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation. Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.